DESCRIPTION (provided by investigator): Each year, 500 million are infected and 1 million die because of malaria, with most deaths due to cerebral malaria in African children. In sub-Saharan Africa, roughly 24.4 million people have HIV, including 2 million children. Thus, millions are at risk for coinfection with both HIV and malaria, and effects of one infection on the disease course of the other may have global health implications. HIV and malaria each interact with the host's immune system uniquely, resulting in complex activations of immune cells, and subsequent tightly regulated production of cytokines and antibodies. While early population-based studies showed no difference in outcomes between HIV-positive and negative individuals with malaria, more recent work suggests HIV-infected people have more frequent episodes of symptomatic malaria and malaria in those with HIV increases HIV viremia and decreases CD4+ T cells. The effects of co-infection on CNS pathology, including cerebral malaria and HIV-associated neurocognitive disorders, are not known. We hypothesize that HIV and malaria co-infection exacerbates the host immune response, and that this immune dysregulation explains differences in the clinical spectrum of disease. In this proposal, we will use established in vitro and in vivo experimental models to examine the mechanisms by which co-infection causes immune dysregulation and how this impacts endothelial activation and blood-brain barrier function. PUBLIC HEALTH RELEVANCE: Both malaria and HIV affect millions of people in the developing world. The majority of malaria deaths are due to cerebral malaria in children in sub-Saharan Africa, where roughly 24.4 million people are infected with HIV, including 2 million children. Recent work suggests HIV-infected people have more frequent episodes of symptomatic malaria, and co-infection with malaria increases HIV viremia and decreases CD4+ T cells. We propose to study how malaria and HIV interact to alter immune function and development of severe malaria including cerebral malaria, as well as progression of HIVassociated neurocognitive disorders. Our long-term goal is to develop interventions that improve clinical outcomes in individuals affected by both malaria and HIV.